TOL has been shown to reduce bladder hyperactivity in patients suffering from urinary incontinence and exerts a spasmolytic effect on bladder smooth muscle by inhibiting the action of acetylcholine on smooth muscle. TOL has selectivity for muscarinic receptors over nicotinic acetylcholine receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions. Like TOL, the active metabolite of TOL, called 5HM, exerts potent and non-selective inhibition of muscarinic receptors (Gillberg, P-G & Sundquist S.: Pharmacological profile of DD01 and desethyloxybutynin (DEOB)—the major metabolite of tolterodine and oxybutynin. J. Urol. 1997, 157: Abstract 312.)
The compounds DES-TOL and 5-HM have been described as major metabolites of TOL by several investigators, such as for example Nilvebrant et al. 1997 (Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol 81:169–172), Brynne et al. 1997 (Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity. Int J Clin Pharmacol Ther 35: 287–295), Andersson et al. 1998 (Biotransformation of tolterodine, a new muscarinic antagonist, in mice, rats, and dogs. Drug Metab Dispos. 26:528–535) and Postlind et al 1998 (Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 26: 289–293).
Prodrugs or precursors of various types, such as for example of the type described by Sparf et al (EP 0957 073 A1) for the active metabolite of TOL, can be prepared for the compounds of the present invention by persons knowledgeable in the art of synthetic chemistry and such prodrugs or precursors are included in the present invention.
Work on non-cholinergic drugs for urinary incontinence has resulted in the compound S-TOL that was found to express non-cholinergic spasmolytic activities, while expressing little anticholinergic activity at pharmacological dose-levels (U.S. Pat. No. 6,310,103). The secondary amine metabolite of tolterodine (des-isopropyl-tolterodine or DES-TOL and particularly the corresponding S-isomer) was found to express non-cholinergic spasmolytic activities while the anticholinergic activity was further decreased (U.S. patent Ser. No. 09/775,060). The present invention represents another important step since the compounds of the present invention have surprisingly been found to be potent spasmolytic compounds, while being completely free from anticholinergic effects in pharmacological dose levels. Additionally, the compounds of the present invention are surprisingly free from cardiovascular side effects.
In this document, an optically pure compound or a compound being substantially free from its distomer implies an optical purity of at least 96%, preferably better than 98%.